Stabilization of poly(oxyalkylene) containing polymeric materials

ABSTRACT

The present invention provides a method for producing a medical device, preferably an ophthalmic device, more preferably a contact lens, made of a stabilized poly(oxyalkylene)-containing polymeric material. The method of the invention comprises the steps of: curing, in a mold, a composition comprising (a) a prepolymer having at least one poly(oxyalkylene) unit, (b) a biocompatible organic multi-acid or biocompatible salt thereof in an amount sufficient to improve the stability of the poly(oxyalkylene)-containing polymer made from the composition, (c) optionally a photoinitiator or a thermal initiator, and (d) optionally one or more vinylic monomers, to form the medical device being less susceptible to oxidative degradation; and removing the medical device from the mold.

[0001] This application claims the benefits under 35 USC § 119 (e) ofU.S. provisional application Nos. 60/429,719 filed Nov. 27, 2002 and60/512,591 filed Oct. 17, 2003, incorporated by reference in theirentireties.

[0002] The present invention relates to stabilization ofpoly(oxyalkylene)-containing polymeric materials. More specifically, thepresent invention relates to a method for stabilizing apoly(oxyalkylene)-containing polymeric material; a method for making amedical device, preferably an ophthalmic device, containing a stabilizedpoly(oxyalkylene)-containing polymeric material; a method forsterilizing a medical device having a core and/or a coating made of apoly(oxyalkylene)-containing polymeric material, wherein the method ischaracterized by having an improved stability of thepoly(oxyalkylene)-containing polymeric material. In addition, thepresent invention relates to a stabilized poly(oxyalkylene)-containingpolymeric material; a medical device comprising a core or a coating madeof a stabilized poly(oxyalkylene)-containing polymeric material; and asolution for sterilizing and/or storing a medical device having a coreor a coating made of a poly(oxyalkylene)-containing polymeric material,wherein the solution is capable of stabilizing thepoly(oxyalkylene)-containing polymeric material.

BACKGROUND OF THE INVENTION

[0003] Because of the biocompatibility of poly(alkyleneglycols), alsoknown as polyalkyl ethers or poly(alkylene oxide),poly(oxyalkylene)-containing polymers can find use in various fields, inparticular in biomedical fields, such as, for example, carriers fordrug-delivery, artificial tissues, dentifrices, contact lenses,intraocular lenses, and other biomedical devices. (For a recent reviewof applications see the ACS Symposium Series 680, “Poly(ethyleneglycol):Chemistry and Biological Applications”, 1997, Harris and Zalipsky, eds.)However, poly(oxyalkylene)-containing polymers may be susceptible todegradation, in particular, oxidative degradation of itspoly(oxyalkylene) chains under aerobic conditions. Oxidative degradationmay cause changes in the properties of an article made from thepoly(oxyalkylene)-containing polymers and limit the applications ofpoly(oxyalkylene)-containing polymers.

[0004] Susceptibility to oxidative degradation of apoly(oxyalkylene)-containing polymer can be effected by the method usedin preparation and purification, post-manufacturing process (e.g.,sterilization with autoclave, or the like), storage, and use. It isgenerally believed that, under aerobic conditions, apoly(oxyalkylene)-containing polymer may be degraded according to themechanism of a free-radical chain reaction involving an oxidation step(see “Stability of the Polyoxyethylene Chain”, Donbrow, Max. SurfactantSci. Ser. (1987), 23 (Nonionic Surfactants), 1011-1072, and referencescontained therein). First, homolytic degradation of the alkylene glycolchain in a poly(oxyalkylene)-containing polymer is initiatedphotochemically, thermally, or chemically (e.g., by actinic radiationincluding UV radiation, ionizing radiation, or microwave, at elevatedtemperatures, or with free-radical initiators, etc.), producing analkylene glycol radical. This radical undergoes spontaneous oxidationunder aerobic conditions to form peroxides and hydroperoxides. Theresulting peroxides and hydroperoxides may then undergo a variety ofsubsequent reactions to yield by-products such as formic acid, loweralcohols, and the like. For a contact lens made from apoly(oxyalkylene)-containing polymer, the poly(oxyalkylene) chain of thepoly(oxyalkylene)-containing polymer may be susceptible to oxidativedegradation, leading to formation of by-products such as formic acid andothers. These by-products, especially formic acid which can haveirritating effects, are not desirable, and thus need to be eliminated orminimized. Moreover, a medical device made from apoly(oxyalkylene)-containing polymer may have a shorter shelf lifebecause of oxidative degradation of the poly(oxyalkylene)-containingpolymer.

[0005] There have been attempts to stabilizepoly(oxyalkylene)-containing materials used for medical devices by usingantioxidants. For example, see U.S. Pat. Nos. 5,290,585, 5,160,790,5,179,186, 5,367,001, 4,886,866 and 5,175,229, and EP 0333899B1. Theantioxidants disclosed in those patents are hindered phenolic compounds,such as butylated hydroxytoluene, tris (3,5-di-t-butyl-4- hydroxybenzyl) isocyanurate, 2,2′-methylenebis (4-methyl-6-t-lutyl phenol),1,3,5-Trimethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl) benzene,octadecyl 3,5, di-t-butyl-4-hydroxyhydrocinnamate, 4,4 methylenebis(2,6-di-t-butylphenol), p,p-dioctyl diphenylamine,1,1,3-tris-(2-methyl-4-hydroxy-5-t-butylphenyl) butane, Irganox (CibaGeigy), and Santonox (Monsanto Corp.). However, there are somedisadvantages associated with those antioxidants in the prior art forstabilizing poly(oxyalkylene)-containing materials. Those antioxidantsmay not be suitable for applications where the device is remain incontact with living tissues for long periods of times due to theircytotoxicity, or are water insoluble so that they can not be used in awater-base formulation for making the poly(oxyalkylene)-containingmaterials. Furthermore, those antioxidants may not be efficient instabilizing poly(oxyalkylene)-containing materials and/or reducing thelevels of by-products such as formic acid, in case where thepoly(oxyalkylene)-containing materials are used to make contact lensesor other medical devices.

[0006] Accordingly, there is still a need for a method for stabilizingpoly(oxyalkylene)-containing polymeric materials using a biocompatiblematerial. Such stabilized poly(oxyalkylene)-containing polymericmaterials can find particular use in making a medical device which arein contact with living cells or tissues.

SUMMARY OF THE INVENTION

[0007] One object of the invention is to provide a method forstabilizing a poly(oxyalkylene)-containing polymeric material using oneor more biocompatible materials.

[0008] Another object of the invention is to provide a method forproducing a stabilized poly(oxyalkylene)-containing polymeric material.

[0009] Still another object of the invention is to provide a method or acomposition for making a medical device from a stabilizedpoly(oxyalkylene)-containing polymeric material.

[0010] A further object of the invention is to provide a stabilizedpoly(oxyalkylene)-containing polymeric material and a medical devicemade from a stabilized poly(oxyalkylene)-containing polymeric material.

[0011] A still further object of the invention is to provide a methodfor sterilizing a medical device made of a poly(oxyalkylene)-containingpolymeric material while improving the stability of thepoly(oxyalkylene)-containing polymeric material.

[0012] These and other objects of the invention are met by the variousaspects of the invention described herein.

[0013] In accomplishing the foregoing, there is provided, in accordancewith one aspect of the present invention, a stabilizedpoly(oxyalkylene)-containing polymeric material, which comprises: (a) apolymer network having at least one unit of formula (I)

—O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I)

[0014] wherein R₁, R₂, and R₃, independently of one other, are eachlinear or branched C₂-C₆-alkylene, and n, m and p, independently of oneanother, are each a number from 0 to 100, wherein the sum of (n+m+p) is5 to 1000, preferably 5 to 500, more preferably 5 to 200, even morepreferably 8 to 120; and (b) a biocompatible organic multi-acid orbiocompatible salt thereof present in an amount sufficient to improvethe stability of the poly(oxyalkylene)-containing polymeric material,wherein the biocompatible organic multi-acid or biocompatible saltthereof is distributed within the polymeric material but not crosslinkedto the polymer network. Preferably, the biocompatible organic multi-acidor biocompatible salt thereof is present in an amount effective toimpart to the medical device a decreased susceptibility to oxidativedegradation characterized by having at least an 1.5-fold reduction ofthe amount of detectable formic acid and optionally other degradationby-products.

[0015] In another aspect, the present invention provides a medicaldevice comprising a poly(oxyalkylene)-containing polymeric material anda biocompatible organic multi-acid or biocompatible salt thereof presentin an amount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymeric material, wherein thepoly(oxyalkylene)-containing polymeric material has a polymer networkhaving at least one unit of formula (I), and wherein the biocompatibleorganic multi-acid or biocompatible salt thereof is distributed withinthe poly(oxyalkylene)-containing polymeric material but not crosslinkedto the polymer network. Preferably, the biocompatible organic multi-acidor biocompatible salt thereof is present in an amount effective toimpart to the medical device a decreased susceptibility to oxidativedegradation characterized by having at least an 1.5-fold reduction ofthe amount of detectable formic acid and optionally other degradationby-products.

[0016] In still another aspect, the present invention provides a methodfor producing a medical device, preferably an ophthalmic device, morepreferably a contact lens, made of a stabilizedpoly(oxyalkylene)-containing polymeric material, the method comprisingthe steps of: (1) obtaining a polymerizable fluid composition comprising(a) a prepolymer having at least one poly(oxyalkylene) unit of formula(I) and ethylenically unsaturated groups, (b) a biocompatible organicmulti-acid or biocompatible salt thereof, (c) optionally aphotoinitiator or a thermal initiator, and (d) optionally one or morevinylic monomers; (2) introducing an amount of the polymerizable fluidcomposition in a mold for making the medical device; and (3) actinicallyor thermally polymerizing the polymerizable fluid composition in themold to form the medical device having a polymer network having at leastone unit of formula (I) and the biocompatible organic multi-acid orbiocompatible salt thereof which is not crosslinked to the polymernetwork, wherein the biocompatible organic multi-acid or biocompatiblesalt thereof is present in an amount effective to improve the stabilityof the medical device so that the medical device has a decreasedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.

[0017] In a further aspect, the present invention provides a method forproducing a medical device, preferably an ophthalmic device, morepreferably a contact lens, made of a stabilizedpoly(oxyalkylene)-containing polymeric material, the method comprisingthe steps of: (1) introducing a reactive mixture into a mold for makingthe medical device by using a Reaction Injection Molding (RIM) processto form the medical device, wherein the reactive mixture comprises (a)at least one monomer or prepolymer having at least one poly(oxyalkylene)unit of formula (I) and functional groups which are amino, carboxy,hydroxyl or isocyanato groups and (b) at least one of an organicdiamine, an organic polyamine, an organic diacid, an organic polyacid,an organic diol, an organic polyol, an organic diisocyante, and organicpolyisocyanate, provided that components (a) and (b) react with eachother to form a polyurea and/or polyurethane network; (2) removing themedical device from the mold; and (3) impregnating the medical devicewith a biocompatible organic multi-acid or biocompatible salt thereof inan amount effective to improve the stability of the medical device sothat the medical device has a decreased susceptibility to oxidativedegradation characterized by having at least an 1.5-fold reduction ofthe amount of detectable formic acid and optionally other degradationby-products.

[0018] In another further aspect, the present invention provides amethod for sterilizing a medical device which comprises a core materialand/or a coating, wherein the core material and the coating,independently from each other, are made of apoly(oxyalkylene)-containing polymeric material, the method comprising:autoclaving the medical device in an aqueous solution containing abiocompatible organic multi-acid or biocompatible salt thereof in anamount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymeric material, so that thepoly(oxyalkylene)-containing polymeric material has a decreasedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.

[0019] In still a further aspect, the present invention provides anaqueous solution for sterilizing and/or storing an ophthalmic device,wherein the ophthalmic device is made of a poly(oxyalkylene)-containingpolymeric material, the aqueous solution having: a biocompatible organicmulti-acid or biocompatible salt thereof in an amount sufficient toimprove the stability of the poly(oxyalkylene)-containing polymericmaterial; an osmolarity of about 200 to 450 milli-osmole in 1000 ml(unit: mOsm/ml), wherein the aqueous solution is capable of improvingthe stability of the poly(oxyalkylene)-containing polymeric material, sothat the poly(oxyalkylene)-containing polymeric material has a decreasedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.

[0020] These and other aspects of the invention will become apparentfrom the following description of the preferred embodiments. As would beobvious to one skilled in the art, many variations and modifications ofthe invention may be effected without departing from the spirit andscope of the novel concepts of the disclosure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Reference now will be made in detail to the embodiments of theinvention. It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Forinstance, features illustrated or described as part of one embodiment,can be used on another embodiment to yield a still further embodiment.Thus, it is intended that the present invention cover such modificationsand variations as come within the scope of the appended claims and theirequivalents. Other objects, features and aspects of the presentinvention are disclosed in or are obvious from the following detaileddescription. It is to be understood by one of ordinary skill in the artthat the present discussion is a description of exemplary embodimentsonly, and is not intended as limiting the broader aspects of the presentinvention.

[0022] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Generally, thenomenclature used herein and the laboratory procedures are well knownand commonly employed in the art. Conventional methods are used forthese procedures, such as those provided in the art and various generalreferences. Where a term is provided in the singular, the inventors alsocontemplate the plural of that term. The nomenclature used herein andthe laboratory procedures described below are those well known andcommonly employed in the art.

[0023] An “article” refers to a medical device or a mold for making amedical device.

[0024] A “medical device”, as used herein, refers to a device or a partthereof having one or more surfaces that contact tissue, blood, or otherbodily fluids of patients in the course of their operation or utility.Exemplary medical devices include: (1) extracorporeal devices for use insurgery such as blood oxygenators, blood pumps, blood sensors, tubingused to carry blood and the like which contact blood which is thenreturned to the patient; (2) prostheses implanted in a human or animalbody such as vascular grafts, stents, pacemaker leads, heart valves, andthe like that are implanted in blood vessels or in the heart; (3)devices for temporary intravascular use such as catheters, guide wires,and the like which are placed into blood vessels or the heart forpurposes of monitoring or repair; (4) artificial tissues such asartificial skin for burn patients; (5) dentifrices, dental moldings; (6)ophthalmic devices. In a preferred embodiment, medical devices areophthalmic devices; and (7) cases or containers for storing ophthalmicdevices or ophthalmic solutions.

[0025] An “ophthalmic device”, as used herein, refers to a contact lens(hard or soft), an intraocular lens, a corneal onlay, other ophthalmicdevices (e.g., stents, or the like) used on or about the eye or ocularvicinity.

[0026] “Biocompatible”, as used herein, refers to a material or surfaceof a material, which may be in intimate contact with tissue, blood, orother bodily fluids of a patient for an extended period of time withoutsignificantly damaging the ocular environment and without significantuser discomfort.

[0027] “Ophthalmically compatible”, as used herein, refers to a materialor surface of a material which may be in intimate contact with theocular environment for an extended period of time without significantlydamaging the ocular environment and without significant user discomfort.Thus, an ophthalmically compatible contact lens will not producesignificant corneal swelling, will adequately move on the eye withblinking to promote adequate tear exchange, will not have substantialamounts of protein or lipid adsorption, and will not cause substantialwearer discomfort during the prescribed period of wear.

[0028] “Ocular environment”, as used herein, refers to ocular fluids(e.g., tear fluid) and ocular tissue (e.g., the cornea) which may comeinto intimate contact with a contact lens used for vision correction,drug delivery, wound healing, eye color modification, or otherophthalmic applications.

[0029] A “monomer” means a low molecular weight compound that can bepolymerized. Low molecular weight typically means average molecularweights less than 700 Daltons.

[0030] A “vinylic monomer”, as used herein, refers to a low molecularweight compound that has an ethylenically unsaturated group and can bepolymerized actinically or thermally. Low molecular weight typicallymeans average molecular weights less than 700 Daltons. Exemplaryethylenically unsaturated groups include without limitation acryloyl,methacryloyl, allyl, vinyl, styrenyl, or other C═C containing groups.

[0031] A “hydrophilic vinylic monomer”, as used herein, refers to avinylic monomer which as a homopolymer typically yields a polymer thatis water-soluble or can absorb at least 10 percent by weight water.

[0032] A “hydrophobic vinylic monomer”, as used herein, refers to avinylic monomer which as a homopolymer typically yields a polymer thatis insoluble in water and can absorb less than 10 percent by weightwater.

[0033] A “macromer” refers to a medium and high molecular weightcompound or polymer that contains functional groups capable ofundergoing further polymerizing/crosslinking reactions. Medium and highmolecular weight typically means average molecular weights greater than700 Daltons. Preferably, a macromer contains ethylenically unsaturatedgroups and can be polymerized actinically or thermally.

[0034] A “polymer” means a material formed by polymerizing/crosslinkingone or more monomers.

[0035] A “prepolymer” refers to a starting polymer which can be cured(e.g., crosslinked and/or polymerized) actinically or thermally orchemically to obtain a crosslinked and/or polymerized polymer having amolecular weight much higher than the starting polymer.

[0036] Preferably, a prepolymer contains ethylenically unsaturatedgroups and can be polymerized actinically or thermally.

[0037] As used herein, “actinically” in reference to curing orpolymerizing of a polymerizable composition or material means that thecuring (e.g., crosslinked and/or polymerized) is performed by actinicirradiation, such as, for example, UV irradiation, ionized radiation(e.g. gamma ray or X-ray irradiation), and microwave irradiation.

[0038] A “photoinitiator” refers to a chemical that initiates radicalcrosslinking/polymerizing reaction by the use of light. Suitablephotoinitiators include, without limitation, benzoin methyl ether,diethoxyacetophenone, a benzoylphosphine oxide, 1-hydroxycyclohexylphenyl ketone, Darocure® types, and Irgacure® types, preferablyDarocure® 1173, and Irgacure® 2959.

[0039] A “thermal initiator” refers to a chemical that initiates radicalcrosslinking/polymerizing reaction by the use of heat energy. Examplesof suitable thermal initiators include, but are not limited to,2,2′-azobis (2,4-dimethylpentanenitrile), 2,2′-azobis(2-methylpropanenitrile), 2,2′-azobis (2-methylbutanenitrile), peroxidessuch as benzoyl peroxide, and the like. Preferably, the thermalinitiator is azobisisobutyronite (AIBN).

[0040] A “stabilized poly(oxyalkylene)-containing polymeric material”means that a poly(oxyalkylene)-containing polymeric material, which isprepared from a composition comprising a stabilizer and/or subjected toa sterilization treatment in a solution containing the stabilizer, isless susceptible to oxidative degradation (i.e., characterized by theamount of detectable formic acid and optionally other degradationby-products in a stabilized poly(oxyalkylene)-containing polymericmaterial being 80% or less, preferably 65% or less, more preferably 50%or less, of that detected in a non-stabilizedpoly(oxyalkylene)-containing polymeric material). A “non-stabilizedpoly(oxyalkylene)-containing polymeric material” means that apoly(oxyalkylene)-containing polymeric material, which is prepared froma composition without the stabilizer and/or subjected to a sterilizationtreatment in a solution without the stabilizer.

[0041] “Improve the stability of a poly(oxyalkylene)-containingpolymeric material” means that the susceptibility to oxidativedegradation of a poly(oxyalkylene)-containing polymeric material, whichis prepared from a composition comprising a stabilizer and/or subjectedto a sterilization treatment in a solution containing the stabilizer, isreduced (characterized by the amount of detectable formic acid andoptionally other degradation by-products in a stabilizedpoly(oxyalkylene)-containing polymeric material being smaller than thatdetected in a non-stabilized corresponding poly(oxyalkylene)-containingpolymeric material). The amount of detectable formic acid and optionallyother degradation by-products derived from oxidative degradation of apoly(oxyalkylene)-containing polymeric material can be determined by anyknown suitable methods, such as, for example, ion-exchangechromatography described in Examples.

[0042] A “decreased susceptibility to oxidative degradation” inreference to a poly(oxyalkylene)-containing polymeric material or amedical device comprising a poly(oxyalkylene)-containing polymericmaterial means that its susceptibility to oxidative degradation isdecreased by having a stabilizer therein. Typically, a decreasedsusceptibility to oxidative degradation of apoly(oxyalkylene)-containing polymeric material or a medical devicecomprising a poly(oxyalkylene)-containing polymeric material ischaracterized by having a stabilizer-induced reduction (preferably atleast an 1.5-fold reduction, more preferably at least a 3-foldreduction, even more preferably at least a 5-fold reduction, mostpreferably at least a 1 0-fold reduction) of the amount of detectableformic acid and optionally other degradation by-products derived fromoxidative degradation of the poly(oxyalkylene)-containing polymericmaterial. An “X-fold reduction of the amount of detectable formic acidand optionally other degradation by-products” means that, when comparinga stabilized poly(oxyalkylene)-containing polymeric material (or astabilized medical device containing a stabilizer) with a correspondingnon-stabilized poly(oxyalkylene)-containing polymeric material (or anon-stabilized medical device without a stabilizer), the amount ofdetectable formic acid and optionally other degradation by-products inthe non-stabilized poly(oxyalkylene)-containing polymeric material (orthe non-stabilized medical device) is at least X folds of the amount ofdetectable formic acid and optionally other degradation by-products inthe stabilized poly(oxyalkylene)-containing polymeric material (or thestabilized medical device).

[0043] An “interpenetrating polymer network (IPN)” as used herein refersbroadly to an intimate network of two or more polymers at least one ofwhich is either synthesized and/or crosslinked in the presence of theother(s). Techniques for preparing IPN are known to one skilled in theart. For a general procedure, see U.S. Pat. Nos. 4,536,554, 4,983,702,5,087,392, and 5,656,210, the contents of which are all incorporatedherein by reference. The polymerization is generally carried out attemperatures ranging from about room temperature to about 145° C.

[0044] The present invention generally relates to a stabilizedpoly(oxyalkylene)-containing polymeric material and methods for makingthe same.

[0045] In one aspect, the present invention provides a stabilizedpoly(oxyalkylene)-containing polymeric material. A stabilizedpoly(oxyalkylene)-containing polymeric material of the inventioncomprises: (a) a polymer network having at least one unit of formula (I)

—O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I)

[0046] wherein R₁, R₂, and R₃, independently of one other, are eachlinear or branched C₂-C₆-alkylene, and n, m and p, independently of oneanother, are each a number from 0 to 100, wherein the sum of (n+m+p) is5 to 1000, preferably 5 to 500, more preferably 5 to 200, even morepreferably 8 to 120; and (b) a biocompatible organic multi-acid orbiocompatible salt thereof present in an amount sufficient to improvethe stability of the poly(oxyalkylene)-containing polymeric material,which is distributed within the polymeric material but not crosslinkedto the polymer network.

[0047] In accordance with the present invention, apoly(oxyalkylene)-containing polymeric material can be any polymer whichis a reaction product of a mixture including a poly(oxyalkylene) polymerwith functional groups (e.g., amino, hydroxyl, acid, or isocyanatogroups) and at least a chemical with functional groups (e.g., amino,hydroxyl, isocyanato, or acid groups) which are co-reactive with thefunctional groups of poly(oxyalkylene) polymer. Examples of such polymerinclude without limitation: (1) a polyester obtained by esterificationof the terminal diols of a hydroxy terminated (diols)poly(oxyalkylene)-containing polymer with organic monoacids or diacidssuch as, for example, glutaric or adipic acids; (2) a polyamide obtainedby reacting an amine terminated poly(oxyalkylene)-containing polymerwith organic monoacids or diacids acids such as, for example, glutaricor adipic acids; (3) a polyurethane which is the copolymerizationproduct of a mixture comprising one or more hydroxyl (orisocyanate)-terminated poly(oxyalkylene)-containing polymer and one ormore organic di- or polyisocyanates (or diols or polyols); (4) apolyurea which is the copolymerization product of a mixture comprisingone or more amine (or isocyanate)-terminatedpoly(oxyalkylene)-containing polymer and one or more di- ormulti-isocyanates (or diamines or polyamines); and apolyurea/polyurethane which is the copolymerization product of a mixturecomprising one or more amine or hydroxy-terminatedpoly(oxyalkylene)-containing polymer, one or more di- ormulti-isocyanates and one or more organic di-or polyamines (or di- orpolyols). The above examples have been given as a means of illustratingthe aspects of the invention and are not limiting in any way. It shouldbe understood that a poly(oxyalkylene)-containing polymeric material canalso contain one or more silicone and/or fluorine atoms.

[0048] In accordance with the present invention, apoly(oxyalkylene)-containing polymeric material can also be aninterpenetrating or semi-interpenetrating polymer network. Exemplaryinterpenetrating polymer networks are interpenetratingpolyurea/polyacrylic networks disclosed in EP 0735097 B1. Suchinterpenetrating polyurea/polyacrylic networks are formed bypolymerizing a reactive mixture comprising: (a) at least oneamine-terminated poly(alkylene glycol); (b) an organic di- orpolyisocyanate which reacts with (a) to form a polyurea network; (c) anacrylic ester; (d) a free radical initiator to polymerize (c) to form apolyacrylic network; and (e) a triamine to crosslink (a).

[0049] Exemplary poly(alkylene glycol), include, but are not limited to,a poly(ethylene glycol), a poly(1-propylene glycol), a poly(2-propyleneglycol), a poly(ethylene glycol)/poly(propylene glycol) block polymer, apoly(ethylene glycol)/poly(propylene glycol )/poly(butylene glycol)block polymer, a polytetrahydrofuran, a poloxamer, and the like.

[0050] In accordance with the present invention, a stabilizedpoly(oxyalkylene)-containing polymeric material has a decreasedsusceptibility to oxidative degradation, characterized by havingpreferably at least an 1.5-fold reduction of, more preferably at least a3-fold reduction, even more preferably at least a 5-fold reduction of,most preferably at least 10-fold reduction of the amount of detectableformic acid and optionally other degradation by-products.

[0051] Any known suitable organic multi-acids or biocompatible saltsthereof, which are water-soluble, non-toxic, biocompatible, and capableof stabilizing poly(oxyalkylene) chains in the presence of UV light orfree radical sources or at high temperatures. Exemplary organicmulti-acids suitable for the present invention include, but are notlimited to, hydroxy diacids, hydroxy multi-acids, amino acids, and thelike. Preferably, an organic multi-acid of the present invention is anα-oxo-multi-acid, such as, for example, citric acid, 2-ketoglutaricacid, or malic acid. More preferably, an organic multi-acid is citric ormalic acid. Biocompatible (preferably ophthalmically compatible) saltsof organic multi-acids suitable for the present invention includesodium, potassium, and ammonium salts.

[0052] As used herein, an “alpha-oxo-multiacid” refers to an acid whichhas a plurality (two or more) of carboxyl groups and at least one carbonatom which is simultaneously substituted by a carboxyl group and anoxygen atom, i.e., O—C—COOR, wherein the oxygen could be a carbonyl, ahydroxy, an esterified hydroxy, an ether, or the like, and wherein theoxygen is on the carbon which is alpha to the carboxyl group.

[0053] In accordance with the present invention, a biocompatible organicmulti-acid or biocompatible salt thereof can be introduced into astabilized poly(oxyalkylene)-containing polymeric material either byadding it into a pre-polymerization composition for making thepoly(oxyalkylene)-containing polymeric material and/or by immersing apoly(oxyalkylene)-containing polymeric material in a solution containingthe biocompatible organic multi-acid or biocompatible salt thereof(i.e., impregnation of the poly(oxyalkylene)-containing polymericmaterial with the biocompatible organic multi-acid or biocompatible saltthereof.

[0054] The concentration of a biocompatible organic multi-acid orbiocompatible salt thereof in a pre-polymerization composition formaking a stabilized poly(oxyalkylene)-containing polymeric material orin a solution for impregnation of the poly(oxyalkylene)-containingpolymeric material with the biocompatible organic multi-acid orbiocompatible salt thereof is preferably from 0.001 millimolar to thesolubility limit of a particular biocompatible organic multi-acid orbiocompatible salt thereof, more preferentially from 10 to 300millimolar. It is understood that the weight percentages will changebased on the molecular weight of the acid employed.

[0055] In a preferred embodiment, a stabilizedpoly(oxyalkylene)-containing polymeric material of the invention is acopolymerization product of a composition comprising:

[0056] (a) a prepolymer containing ethylenically unsaturated groups andat least one unit of formula (I)

—O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I)

[0057] wherein R₁, R₂, and R₃, independently of one other, are eachlinear or branched C₂-C₄-alkylene, and n, m and p, independently of oneanother, are each a number from 0 to 100, wherein the sum of (n+m+p) is5 to 1000, preferably 5 to 500, more preferably 5 to 200, even morepreferably 8 to 120;

[0058] (b) a water-soluble and biocompatible organic multi-acid orbiocompatible salt thereof in an amount sufficient to improve thestability of the poly(oxyalkylene)-containing polymeric material madefrom the composition;

[0059] (c) optionally a photoinitiator or a thermal initiator; and

[0060] (d) optionally one or more vinylic monomers.

[0061] In another preferred embodiment, a stabilizedpoly(oxyalkylene)-containing polymeric material of the invention is apoly(oxyalkylene)-containing polymeric material impregnated with abiocompatible organic multi-acid or biocompatible salt thereof in anamount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymeric material, wherein thepoly(oxyalkylene)-containing polymeric material is a copolymerizationproduct of a composition comprising:

[0062] (a) a prepolymer containing ethylenically unsaturated groups andat least one unit of formula (I)

—O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I)

[0063] wherein R₁, R₂, and R₃, independently of one other, are eachlinear or branched C₂-C₄-alkylene, and n, m and p, independently of oneanother, are each a number from 0 to 100, wherein the sum of (n+m+p) is5 to 1000, preferably 5 to 500, more preferably 5 to 200, even morepreferably 8 to 120;

[0064] (b) optionally a photoinitiator or a thermal initiator; and

[0065] (c) optionally one or more vinylic monomers.

[0066] Impregnation of a poly(oxyalkylene)-containing polymeric materialcan be performed according to any known suitable methods, for example,such as immersing the poly(oxyalkylene)-containing polymeric material ina solution containing a biocompatible organic multi-acid orbiocompatible salt thereof.

[0067] A prepolymer having at least one unit of formula (I) andethylenically unsaturated groups can be prepared according to anymethods known to a person skilled in the art. For example, ethylenicallyunsaturated groups, such as, for example, acryloyl, methacryloyl, allyl,vinyl, styrenyl, or other C═C containing groups, could be covalentlyattached to the poly(alkylene glycol) moiety according to any methodknown to a person skilled in the art.

[0068] One example of such prepolymer is a crosslinkable polyureapolymer described in U.S. Pat. No. 6,479,587, herein incorporated byreference in its entirety. Such crosslinkable polyurea polymer can beprepared by introducing ethylenically unsaturated groups into a polyureawhich is the copolymerization product of a reaction mixture including atleast one amine-terminated poly(alkylene glycol) and an organic di- orpolyisocyanate.

[0069] A further example is a crosslinkable polyurethane described inU.S. patent application Ser. No. 10/640,294 filed on Aug. 13, 2003(herein incorporated by reference in its entirety). Such crosslinkablepolyurethane polymer can be prepared by introducing ethylenicallyunsaturated groups into an isocyanate-capped polyurethane which is thecopolymerization product of a reaction mixture including at least onehydroxy-terminated poly(alkylene glycol) and an organic di- orpolyisocyanate.

[0070] The vinylic monomer which may be additionally used forphoto-crosslinking in accordance with the invention may be hydrophilic,hydrophobic or may be a mixture of a hydrophobic and a hydrophilicvinylic monomer. Suitable vinylic monomers include especially thosenormally used for the manufacture of contact lenses.

[0071] It is preferable to use a hydrophobic vinylic monomer, or amixture of a hydrophobic vinylic monomer with a hydrophilic vinylicmonomer, whereby this mixture contains at least 50 percent by weight ofa hydrophobic vinyl monomer. In this way, the mechanical properties ofthe polymer may be improved without the water content droppingsubstantially. Both conventional hydrophobic vinylic monomers andconventional hydrophilic vinylic monomers are suitable forcopolymerization with the radiation-curable prepolymers according to theinvention.

[0072] Suitable hydrophobic vinylic monomers include, withoutlimitation; C₁-C₁₈-alkylacrylates and -methacrylates, C₃-C₁₈alkylacrylamides and -methacrylamides, acrylonitrile, methacrylonitrile,vinyl-C₁-C₁₈-alkanoates, C₂-C₁₈-alkenes, C₂-C₁₈-halo-alkenes, styrene,C₁-C₆-alkylstyrene, vinylalkylethers in which the alkyl moiety has 1 to6 carbon atoms, C₂-C₁₀-perfluoralkyl-acrylates and -methacrylates orcorrespondingly partially fluorinated acrylates and methacrylates,C₃-C₁₂-perfluoralkyl-ethyl-thiocarbonylaminoethyl-acrylates and-methacrylates, acryloxy and methacryloxy-alkylsiloxanes,N-vinylcarbazole, C₁-C₁₂-alkylesters of maleic acid, fumaric acid,itaconic acid, mesaconic acid and the like. Preference is given e.g. toC₁-C₄-alkylesters of vinylically unsaturated carboxylic acids with 3 to5 carbon atoms or vinylesters of carboxylic acids with up to 5 carbonatoms.

[0073] Examples of suitable hydrophobic vinylic monomers includemethylacrylate, ethyl-acrylate, propylacrylate, isopropylacrylate,cyclohexylacrylate, 2-ethylhexylacrylate, methylmethacrylate,ethylmethacrylate, propylmethacrylate, vinyl acetate, vinyl propionate,vinyl butyrate, vinyl valerate, styrene, chloroprene, vinyl chloride,vinylidene chloride, acrylonitrile, 1-butene, butadiene,methacrylonitrile, vinyl toluene, vinyl ethyl ether,perfluorohexylethyl-thio-carbonyl-aminoethyl-methacrylate, isobornylmethacrylate, trifluoroethyl methacrylate, hexafluoro-isopropylmethacrylate, hexafluorobutyl methacrylate,tris-trimethylsilyloxy-silyl-propyl methacrylate,3-methacryloxypropyl-pentamethyl-disiloxane andbis(methacryloxypropyl)-tetramethyl-disiloxane.

[0074] Suitable hydrophilic vinylic monomers include, withoutlimitation, hydroxy-substituted lower alkylacrylates and -methacrylates,acrylamide, methacrylamide, lower alkyl-acrylamides and-methacrylamides, ethoxylated acrylates and methacrylates,hydroxy-substituted lower alkyl-acrylamides and -methacrylamides,hydroxy-substituted lower alkylvinyl-ethers, sodium ethylene sulphonate,sodium styrene sulphonate, 2-acrylamido-2-methyl-propane-sulphonic acid,N-vinyl pyrrole, N-vinyl succinimide, N-vinyl pyrrolidone, 2- or 4-vinylpyridine, acrylic acid, methacrylic acid, amino- (whereby the term“amino” also includes quaternary ammonium), mono-lower-alkylamino- ordi-lower-alkylamino-lower-alkyl-acrylates and -methacrylates, allylalcohol and the like. Preference is given e.g. to hydroxy-substitutedC₂-C₄-alkyl(meth)acrylates, five- to seven-membered N-vinyl-lactams,N,N-di-C₁-C₄-alkyl-methacrylamides and vinylically unsaturatedcarboxylic acids with a total of 3 to 5 carbon atoms.

[0075] Examples of suitable hydrophilic vinylic monomers includehydroxyethyl methacrylate, hydroxyethyl acrylate, acrylamide,methacrylamide, dimethylacrylamide, allyl alcohol, vinyl pyridine, vinylpyrrolidone, glycerol methacrylate,N-(1,1-dimethyl-3-oxobutyl)acrylamide, and the like.

[0076] Preferred hydrophobic vinylic monomers are methyl methacrylateand vinyl acetate. Preferred hydrophilic vinylic monomers are2-hydroxyethyl methacrylate, N-vinyl pyrrolidone and acrylamide.

[0077] A photo-initiator or thermal initiator is advantageously added toa composition of the invention. The amount of photo-initiator may beselected from a wide range, whereby an amount of up to 0.05 g/g polymerand especially up to 0.003 g/g polymer has proved favorable.

[0078] A composition of the invention can further comprise a coloradditive which is capable of creating a light colored visibility tint.Such tint can facilitate the handling of ophthalmic lenses. Any knownsuitable color additives can be used. Preferably, copper phthalocyaninis used as a color additive which is capable of creating a light blue orlight green or other light color visibility tint.

[0079] A composition of the invention can optionally comprise otheradditives, such as, for example, a crosslinking agent, an antimicrobialagents, and/or the like.

[0080] Preferably, a composition of the invention is a water-basedcomposition.

[0081] Optionally a solvent may be present in a composition of theinvention. Any known suitable solvents can be used. Exemplary solventsinclude, but are not limited to, alcohols, such as lower alkanols, forexample ethanol or methanol, and furthermore carboxylic acid amides,such as dimethylformamide, dipolar aprotic solvents, such as dimethylsulfoxide or methyl ethyl ketone, ketones, for example acteone orcyclohexanone, hydrocarbons, for example toluene, ethers, for exampleTHF, dimethoxyethane or dioxane, and halogenated hydrocarbons, forexample trichloroethane, and also mixtures of suitable solvents, forexample mixtures of water with an alcohol, for example a water/ethanolor a water/methanol mixture. A person skilled in the art will know howto select a solvent.

[0082] A composition of the invention for preparing a stabilizedpoly(oxyalkylene)-containing polymeric material can find use in making amedical device, preferably an ophthalmic device, more preferably acontact lens.

[0083] In another aspect, the present invention provides a method forproducing a medical device, preferably an ophthalmic device, morepreferably a contact lens, made of a stabilizedpoly(oxyalkylene)-containing polymeric material, the method comprisingthe steps of: (1) obtaining a polymerizable fluid composition comprising(a) a prepolymer having at least one poly(oxyalkylene) unit of formula(I) and ethylenically unsaturated groups, (b) a biocompatible organicmulti-acid or biocompatible salt thereof, (c) optionally aphotoinitiator or a thermal initiator, and (d) optionally one or morevinylic monomers; (2) introducing an amount of the polymerizable fluidcomposition in a mold for making the medical device; and (3) actinicallyor thermally polymerizing the polymerizable fluid composition in themold to form the medical device having a polymer network having at leastone unit of formula (I) and the biocompatible organic multi-acid orbiocompatible salt thereof which is not crosslinked to the polymernetwork, wherein the biocompatible organic multi-acid or biocompatiblesalt thereof is present in an amount effective to improve the stabilityof the medical device so that the medical device has a decreasedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.

[0084] The polymerizable fluid composition can be introduced into a moldby methods known per se, especially conventional dispensing, e.g.dropwise addition in a desired quantity.

[0085] Appropriate disposable molds are made, for example, frompolypropylene. Suitable materials for re-usable mounds are e.g. quartz,sapphire glass or metals.

[0086] If the molded articles to be produced are contact lenses, thesemay be produced in a manner known per se, e.g. in a conventional“spin-casting mold”, as described for example in U.S. Pat. No.3,408,429, or by the so-called full mold process in a static form, asdescribed e.g. in U.S. Pat. Nos. 4,347,198, 5,508,317, 5,583,463,5,789,464, and 5,849,810.

[0087] Crosslinking/polymerizing of the composition may be initiated inthe mold actinically (e.g. by means of actinic radiation, such as UVirradiation, gamma or X-ray irradiation) or thermally.

[0088] Opening of the mold so that the molded article can be removedfrom the mold may take place in a manner known per se.

[0089] If the molded article produced according to the invention is acontact lens which is produced solvent-free from an already purifiedcrosslinkable prepolymer in the absence of vinylic monomers according tothe invention, then after removal of the molded article, it is notnormally necessary to follow up with purification steps such asextraction. This is because the prepolymers employed do not contain anyundesired constituents of low molecular weight; consequently, thecrosslinked product is also free or substantially free from suchconstituents and subsequent extraction can be dispensed with.Accordingly, the contact lens can be directly transformed in the usualway, by hydration, into a ready-to-use contact lens. Appropriateembodiments of hydration are known to the person skilled in the art,whereby ready-to-use contact lenses with very varied water content maybe obtained. The contact lens (in particular, a hydrogel contact lens)is expanded, for example, in water, in an aqueous salt solution,especially an aqueous salt solution having an osmolarity of about 200 to450 milli-osmole in 1000 ml (unit: mOsm/ml), preferably about 250 to 350mOsm/l and especially about 300 mOsm/l, or in a mixture of water or anaqueous salt solution with a physiologically compatible polar organicsolvent, e.g. glycerol. Preference is given to expansions of the articlein water or in aqueous salt solutions.

[0090] The aqueous salt solutions used for hydration are advantageouslysolutions of physiologically compatible salts, such as buffer saltsconventionally used in the field of contact lens care, e.g. phosphatesalts, or isotonizing agents conventionally used in the field of contactlens care, such as in particular alkali halides, e.g. sodium chloride,or solutions of mixtures thereof. One example of an especially suitablesalt solution is an artificial, preferably buffered lachrymal fluid,which is adapted to natural lachrymal fluid as regards pH value andosmolarity, e.g. an unbuffered or preferably buffered common saltsolution, for example buffered by phosphate buffer, whose osmolarity andpH value correspond to the osmolarity and pH value of human lachrymalfluid.

[0091] The aqueous salt solutions used for hydration preferably containbiocompatible organic multi-acids or biocompatible salts thereof in anamount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymer made from the composition.

[0092] The above-defined hydration fluids are preferably at leastsubstantially free from undesired constituents. This is most preferablypure water or an artificial lachrymal fluid as described above.

[0093] If the molded article produced according to the invention is acontact lens which is produced from an aqueous solution of an alreadypurified crosslinkable prepolymer in the absence of vinylic monomersaccording to the invention, then the crosslinked product is likely notto contain any impurities. It is therefore not necessary to carry outsubsequent extraction. Since crosslinking is carried out in anessentially aqueous solution, it is additionally unnecessary to carryout subsequent hydration. The contact lenses obtained by this processare therefore notable, according to an advantageous embodiment, for thefact that they are suitable for their intended usage without extraction.By intended usage is understood, in this context, that the contactlenses can be used in the human eye.

[0094] The contact lenses obtained according to the invention have a lowsusceptibility to oxidative degradation, characterized by having areduced amount of formic acid and/or other degradation by-productsdetected in the contact lenses. They may have a longer shelf life.Moreover, because of reduction in the formation of formic acid, thecontact lenses obtained according to the invention may not causeirritation to the eyes of a wearer.

[0095] Of course, all the above-mentioned advantages apply not only tocontact lenses, but also to other molded articles according to theinvention, for example, an implantable medical device obtained accordingto the invention. The total of the different advantageous aspects duringproduction of the molded articles according to the invention leads tothe suitability of the molded articles in particular as mass-producedarticles, for example, as contact lenses which are for daily use and/orfor weekly use.

[0096] In still another aspect, the present invention provides a methodfor producing a medical device, preferably an ophthalmic device, morepreferably a contact lens, made of a stabilizedpoly(oxyalkylene)-containing polymeric material, the method comprisingthe steps of: (1) introducing a reactive mixture into a mold for makingthe medical device by using a Reaction Injection Molding (RIM) processto form the medical device, wherein the reactive mixture comprises (a) amonomer or prepolymer having at least one poly(oxyalkylene) unit offormula (I) and functional groups which are amino, carboxy, hydroxyl orisocyanato groups and (b) an organic diamine, an organic polyamine, anorganic diacid, an organic polyacid, an organic diol, an organic polyol,an organic diisocyante, or organic polyisocyanate, provided thatcomponents (a) and (b) react with each other to form a polyurea and/orpolyurethane network; (2) removing the medical device from the mold; and(3) impregnating the medical device with a biocompatible organicmulti-acid or biocompatible salt thereof in an amount effective toimprove the stability of the medical device so that the medical devicehas a decreased susceptibility to oxidative degradation characterized byhaving at least an 1.5-fold reduction of the amount of detectable formicacid and optionally other degradation by-products.

[0097] The RIM process is a known molding process wherein two or morestreams of monomers react in the mold to form a polymer; and is welldescribed by L. T. Manzione in The Encyclopedia of Polymer Science andEngineering; 2nd Edition Vol 14, pg. 72, herein incorporated byreference in its entirety.

[0098] In a preferred embodiment, the reactive mixture can furthercomprise one or more prepolymers having ethylenically unsaturated groupsor one or more vinylic monomers to form a different polymer networkwhich interpenetrate with the polyurea and/or polyurethane network.

[0099] In a further aspect, the present invention provides a medicaldevice comprising a poly(oxyalkylene)-containing polymeric material anda biocompatible organic multi-acid or biocompatible salt thereof presentin an amount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymeric material, wherein thepoly(oxyalkylene)-containing polymeric material has a polymer networkhaving at least one unit of formula (I)

—O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—(I)

[0100] in which R₁, R₂, and R₃, independently of one other, are eachlinear or branched C₂-C₆-alkylene, and n, m and p, independently of oneanother, are each a number from 0 to 100, wherein the sum of (n+m+p) is5 to 1000, preferably 5 to 500, more preferably 5 to 200, even morepreferably 8 to 120, and wherein the biocompatible organic multi-acid orbiocompatible salt thereof is distributed within thepoly(oxyalkylene)-containing polymeric material but not crosslinked tothe polymer network. The biocompatible organic multi-acid orbiocompatible salt thereof is present in an amount effective to improvethe stability of the medical device so that the medical device has adecreased susceptibility to oxidative degradation characterized byhaving preferably at least an 1.5-fold reduction of, more preferably atleast a 3-fold reduction of, even more preferably at least a 5-foldreduction, most preferably at least a 10-fold reduction of the amount ofdetectable formic acid and optionally other degradation by-products.

[0101] In a preferred embodiment, the medical device of the invention isa polymerization product of a composition comprising (a) a prepolymercontaining ethylenically unsaturated groups and at least onepoly(oxyalkylene) unit of formula (I); (b) a water-soluble andbiocompatible organic multi-acid or biocompatible salt thereof in anamount sufficient to improve the stability of apoly(oxyalkylene)-containing polymeric material made from thecomposition; (c) optionally a photoinitiator or a thermal initiator; and(d) optionally one or more vinylic monomers.

[0102] In another preferred embodiment, the biocompatible organicmulti-acid or biocompatible salt thereof is impregnated within thepoly(oxyalkylene)-containing polymeric material, wherein thepoly(oxyalkylene)-containing polymeric material is a polymerizationproduct of a reactive mixture comprising (a) at least one monomer orprepolymer having at least one poly(oxyalkylene) unit of formula (I) andfunctional groups which are amino, carboxy, hydroxyl or isocyanatogroups, and (b) at least one of an organic diamine, an organicpolyamine, an organic diacid, an organic polyacid, an organic diol, anorganic polyol, an organic diisocyante, and organic polyisocyanate,provided that components (a) and (b) react with each other to form apolyurea and/or polyurethane network. More preferably, the reactivemixture further comprises one or more vinylic monomers or prepolymerwith ethylenically unsaturated groups. Those monomers or prepolymers canform upon actinical irradiation a different polymer network whichinterpenetrates the polyurea and/or polyurethane network.

[0103] In another further aspect, the present invention provides amethod for sterilizing a medical device which comprises a core materialand/or a coating, wherein the core material and the coating,independently of each other, are made of a poly(oxyalkylene)-containingpolymeric material, the method comprising: autoclaving the medicaldevice in a solution containing a water-soluble and biocompatibleorganic multi-acid or biocompatible salt thereof in an amount sufficientto improve the stability of the poly(oxyalkylene)-containing polymericmaterial, so that the poly(oxyalkylene)-containing polymeric materialhas a decreased susceptibility to oxidative degradation characterized byhaving at least an 1.5-fold reduction of the amount of detectable formicacid and optionally other degradation by-products.

[0104] A medical device can be coated with apoly(oxyalkylene)-containing material according to any methods known toa person skilled in the art. Exemplary coating techniques include, butare not limited to, dip coating, spraying coating, painting,knife-coating, and printing.

[0105] In still a further aspect, the present invention provides anaqueous solution for sterilizing and/or storing an ophthalmic device,wherein the ophthalmic device is made of a poly(oxyalkylene)-containingpolymeric material, the aqueous solution having: a biocompatible organicmulti-acid or biocompatible salt thereof in an amount sufficient toimprove the stability of the poly(oxyalkylene)-containing polymericmaterial; an osmolarity of about 200 to 450 milli-osmole in 1000 ml(unit: mOsm/ml), wherein the aqueous solution is capable of improvingthe stability of the poly(oxyalkylene)-containing polymeric material, sothat the poly(oxyalkylene)-containing polymeric material has a reducedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.

[0106] An aqueous solution of the invention has an osmolarity of,preferably from about 250 to 350 mOsm/l, more preferably about 300mOsm/l. An aqueous solution of the invention can comprisephysiologically compatible salts, such as buffer salts conventionallyused in the field of contact lens care, e.g. phosphate salts, orisotonizing agents conventionally used in the field of contact lenscare, such as in particular alkali halides, e.g. sodium chloride. Anaqueous solution of the invention can further comprise a physiologicallycompatible polar organic solvent, e.g. glycerol.

[0107] The previous disclosure will enable one having ordinary skill inthe art to practice the invention. In order to better enable the readerto understand specific embodiments and the advantages thereof, referenceto the following non-limiting examples is suggested. However, thefollowing examples should not be read to limit the scope of theinvention.

EXAMPLE 1

[0108] 68.63 g of Jeffamine XTJ-501, 16.04 g of Jeffamine XTJ-502 (bothfrom Huntsman Corporation), and 2.14 g of diethylene triamine (AldrichChemicals) were weighed in a jacketed 1-L reactor. 370 g oftetrahydrofuran (Aldrich) and 200 g of deionized water were added to thereactor and the contents were stirred to be dissolved. A sample wastaken for titration (0.332 mAeq/g vs. 0.335 by theory). The reactor wasthen chilled to 0° C. with stirring under nitrogen. 21.74 g ofisophorone diisocyanate (Aldrich Chemicals, used as received) was thendissolved in 35 g of THF and added dropwise over 45 minutes. Thesolution was stirred at temperature for one hour, and then a sample waswithdrawn and titrated (0.033 mAeq/g vs. 0.035 theory). 3.5 g ofcyclohexylisocyanate (Aldrich Chemicals, used as received) was thenadded in one portion, and the reactor was stirred at 0° C. for one hour.The product was then decanted to a 2-L flask, and the reactor was chasedwith 400 mL of water. The combined products were concentrated on arotary evaporator at 53° C./80 mBar ultimate vacuum to yield a solutionessentially free of tetrahydrofuran. This solution was thenultrafiltered with 20 L of water using a 3-kilodalton membrane. Theresulting purified solution was then concentrated to 50% solids on arotary evaporator.

EXAMPLE 2

[0109] 70 g of Poly(ethylene glycol) with a molecular weight ofapproximately 2000, available from Aldrich Chemicals, was dissolved in70 g of water.

EXAMPLE 3

[0110] 2.00 g of Sodium Ascorbate (Aldrich) was dissolved in 20 g withwater. pH was adjusted to 6.92 by addition of 100 μL of 10% Ascorbicacid in water (Aldrich Chemicals). 1.00 g of Irgacure®-2959(2-Hydroxy-4′-(2-hydroxyethyl)-2-methylpropiophenone, available fromCiba Specialty Chemicals) was mixed with 8.83 g of the ascorbate buffer,and then diluted to 100 g with water. The mixture was dissolved withgentle heating and agitation to provide a clear solution.

EXAMPLE 4

[0111] 2.00 g of Sodium Citrate Dihydrate (Aldrich) was dissolved in 20g with water. pH was adjusted to 7.04 by addition of ˜300 μL of sodiumdihydrogencitrate (Aldrich Chemicals) which was 10% in water. 1.00 g ofIrgacure®-2959 was mixed with 13.11 g of the citrate buffer, and thendiluted to 100 g with water. The mixture was dissolved with gentleheating and agitation to provide a clear solution.

EXAMPLE 5

[0112] 2.00 g of sorbitol (Aldrich Chemicals) was dissolved in 20 g withwater. 1.00 g of Irgacure®-2959 was mixed with 8.12 g of the sorbitolsolution, and then diluted to 100 g with water. The mixture wasdissolved with gentle heating and agitation to provide a clear solution.

EXAMPLE 6

[0113] 1.875 g of 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, freeradical (hereafter, 4-hydroxy-TEMPO) was dissolved in 25 mL of water.

EXAMPLE 7

[0114] 1.00 g of Irgacure 2959 (Ciba Specialty Chemicals) was dissolvedin 99.00 g of water.

EXAMPLE 8

[0115] 10.00 g of polymer from Example 2 was mixed with 0.7425 of thesolution from Example 7 and diluted to 12.00 g with water to afford aPEG/Irgacure® mixture at a ratio of 100:0.15.

EXAMPLE 9

[0116] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of thesolution from Example 7 and diluted to 12.00 g with water to afford aPEG/Irgacure® mixture.

EXAMPLE 10

[0117] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of thesolution from Example 3 and diluted to 12.00 g with water to afford aPEG/Irgacure® mixture containing ascorbate.

EXAMPLE 11

[0118] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of thesolution from Example 4 and diluted to 12.00 g with water to afford aPEG/Irgacure® mixture containing citrate.

EXAMPLE 12

[0119] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of thesolution from Example 5 and diluted to 12.00 g with water to afford aPEG/Irgacure® mixture containing sorbitol.

EXAMPLE 13

[0120] 10.00 g of polymer from Example 2 was mixed with 1.8960 g of thesolution from Example 6 and diluted to 12.00 g with water to afford aPEG/Irgacure® mixture containing 4-hydroxy-TEMPO.

EXAMPLE 14

[0121] 10.00 g of polymer from Example 1 was mixed with 0.7425 of thesolution from Example 7 and diluted to 12.00 g with water to afford aPEG-Urea/Irgacure® mixture at a ratio of 100:0.15.

EXAMPLE 15

[0122] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of thesolution from Example 7 and diluted to 12.00 g with water to afford aPEG-Urea/Irgacure® mixture.

EXAMPLE 16

[0123] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of thesolution from Example 3 and diluted to 12.00 g with water to afford aPEG-Urea/Irgacure® mixture containing ascorbate.

EXAMPLE 17

[0124] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of thesolution from Example 4 and diluted to 12.00 g with water to afford aPEG-Urea/Irgacure® mixture containing citrate.

EXAMPLE 18

[0125] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of thesolution from Example 5 and diluted to 12.00 g with water to afford aPEG-Urea/Irgacure® mixture containing sorbitol.

EXAMPLE 19

[0126] 10.00 g of polymer from Example 1 was mixed with 1.8960 g of thesolution from Example 6 and diluted to 12.00 g with water to afford aPEG-Urea/Irgacure® mixture containing 4-hydroxy-TEMPO.

[0127] Each of the above parent samples from Examples 8-19 were thendivided into four. Samples with the above example numbers with nosuffix(e.g., Example-11) were simply held under refrigeration. Sampleswith the above lot numbers suffixed with “T” (e.g., Example-11-T) wereautoclaved in the dark at 121° C./30 minutes. Samples with the above lotnumbers suffixed with “P” (e.g., Example-11-P) were subjected to 25minute exposure to UV light. Samples of the above lot numbers suffixedwith “PA” (e.g., Example-11-PA) were subjected to 25 minute exposure toUV light, followed by autoclave at 121° C./30 minutes.

[0128] UV light exposure was accomplished using a Macam Lamp with aPhillips HPA 400/30 S Sunlamp bulb. The output of the lamp was capturedby an EFOS® Liquid Light Guide and focused on a cylindrical cell quartzcuvette available from Aldrich Chemicals as part number Z27696-0. Thecuvette was filled with test substance and placed atop an assemblydirectly under the liquid light guide. Lamp intensity was ca. 1.8mW/cm², and exposure time was 25 minutes, implying exposure dose of 2.7J/cm².

[0129] The above-described samples were analyzed by Ion-ExchangeChromatography. The column used was an ICSep ICE-ORH-801 (0.65×300 mm)Transgenomic, P/N ICE-99-9754. The mobile phase was 10 mN H₂SO₄ at aflow rate of 0.8 mL/min. UV detection (λ=205 nm) was used to quantitateformic acid and total unknowns; Refractive Index detection was used toquantitate formaldehyde (sensitivity=512 mv). Injection volume was 100μL and run time was 240 minutes. TABLE 1 Sample Polymer AmendmentTreatment HCOOH HC(O)H IC Unknowns Example 8 PEG-2000 0.15% InitiatorNitrogen 300 1579 3387845 Example 8 P PEG-2000 LS-1 UV 284 226 4089917Example 8 T PEG-2000 Autoclaved  56 247 1460 1600472 Example 8 PAPEG-2000 autoclaved + LS-1 UV 319 165 234 3387845 Example 9 PEG-20000.38% Initiator Nitrogen ND 276 4019 1561001 Example 9 P PEG-2000 LS-1UV ND 308 466 9413559 Example 9 T PEG-2000 Autoclaved 156 272 37861625876 Example 9 PA PEG-2000 autoclaved + LS-1 UV 219 217 442 8508847Example 10 PEG-2000 Ascorbate Buffer Nitrogen 291 4146 1759608 Example10 P PEG-2000 LS-1 UV 337 136 21333767  Example 10 T PEG-2000 Autoclaved 51 301 3822 1451887 Example 10 PA PEG-2000 autoclaved + LS-1 UV 250 38019728127  Example 11 PEG-2000 Citrate Buffer Nitrogen 317 3825 1799368Example 11 P PEG-2000 LS-1 UV 339 482 8699143 Example 11 T PEG-2000Autoclaved 339 3747 1425557 Example 11 PA PEG-2000 autoclaved + LS-1 UV290 554 8110747 Example 12 PEG-2000 Sorbitol Nitrogen 299 3967 1679516Example 12 P PEG-2000 LS-1 UV 243 375 7442590 Example 12 T PEG-2000Autoclaved 188 228 3723 1421715 Example 12 PA PEG-2000 autoclaved + LS-1UV 240 193 432 7803607 Example 13 PEG-2000 TEMPO Nitrogen 286 35861715501 Example 13 P PEG-2000 LS-1 UV 306 466 9072232 Example 13 TPEG-2000 Autoclaved 302 2885 1155402 Example 13 PA PEG-2000 autoclaved +LS-1 UV 156 266 692 9481513

[0130] Table 1 shows results of ion-exchange chromatography of samplesgenerated in Examples 11-16. All results expressed in parts-per-million(μg/mL). A blank entry means that the analyte concentration was belowthe detection limit (50 ppm for formic acid) TABLE 2 Sample PolymerAmendment Treatment HCOOH HC(O)H Irgacure Unknowns Example 14 PEG-Urea0.15% Irgacure Nitrogen 989  626725 Example 14 P PEG-Urea LS-1 UV 78 2021205303 Example 14 T PEG-Urea Autoclaved 1364 1021780 Example 14 PAPEG-Urea autoclaved + LS-1 UV 195 243  869404 Example 15 PEG-Urea 0.38%Irgacure Nitrogen 2842  448187 Example 15 P PEG-Urea LS-1 UV 533 7932312Example 15 T PEG-Urea Autoclaved 4690  475180 Example 15 PA PEG-Ureaautoclaved + LS-1 UV 136 868 7232686 Example 16 PEG-Urea AscorbateBuffer Nitrogen 3593  697009 Example 16 P PEG-Urea LS-1 UV 69 16521371459  Example 16 T PEG-Urea Autoclaved 4235  799883 Example 16 PAPEG-Urea autoclaved + LS-1 UV 60 380 16135664  Example 17 PEG-UreaCitrate Buffer Nitrogen 3170  535949 Example 17 P PEG-Urea LS-1 UV 6627178992 Example 17 T PEG-Urea Autoclaved 3919  669291 Example 17 PAPEG-Urea autoclaved + LS-1 UV 74 521 5752951 Example 18 PEG-UreaSorbitol Nitrogen 3238  614870 Example 18 P PEG-Urea LS-1 UV 746 7979709Example 18 T PEG-Urea Autoclaved 4499  629794 Example 18 PA PEG-Ureaautoclaved + LS-1 UV 124 551 5327765 Example 19 PEG-Urea TEMPO Nitrogen3178  499934 Example 19 P PEG-Urea LS-1 UV 439 4215228 Example 19 TPEG-Urea Autoclaved 5232  504369 Example 19 PA autoclaved + LS-1 UV 104595 5215616

[0131] Table 2 shows results of ion-exchange chromatography of samplesgenerated in Examples 14-19. All results expressed in parts-per-million(μg/mL). A blank entry means that the analyte concentration was belowthe detection limit.

[0132] As can be seen from the tables, the levels of formic acid in theirradiated and autoclaved samples were highest for any given family ofsamples. Furthermore, a second by-product of degradation, formaldehyde,was present in PEG materials of Examples 8-13, whereas formaldehyde wasnot detected in any PEG-urea polymers in Examples 14-19 (Table 2). Thenature of the amendment added to the formulation had dramatic effects onby-product generation during the curing/autoclaving steps. As can beseen, sorbitol, whose hydroxyl groups should act as chain transferagents, had very little efficacy as a stabilizer. The free-radicalscavenger TEMPO had a modest effect on lowering the amount of detectableby-products, reducing them by approximately 25%. But the ascorbate andcitrate buffered formulations had little or no detectable formic acid inany of the samples, indicating a large stabilizing effect brought bythese materials. The efficacy of these two stabilizers versus the moreconventional stabilizers sorbitol and TEMPO was unexpected.

[0133] There is a difference between the two buffers in terms of sideeffects. This was conveniently quantified by monitoring the “totalunknowns” in the chromatograms. These unknowns have been partiallycharacterized in that they are known to represent Irgacure decompositionproducts, high-molecular weight fragments of degraded polymer, and thelike. In general, non-irradiated samples had total unknowns on the orderof 2×10⁶ counts; on irradiation, the unknowns increased to about 9×10⁶counts. Citrate-buffered PEG followed this trend with 1.8×10⁶ countsbefore irradiation and 8.7×10⁶ counts after irradiation and autoclave.Ascorbate buffered polyethylene glycol, however, showed an unknownslevel of 1.8×10⁶ counts before irradiation and 21.3×10⁶ counts after, aten-fold increase. All of the trends observed for the PEG were observedfor the PEG Urea. There was thus a large and unexpected stabilization ofPEG and PEG-Urea in the presence of an organic multi-acid of the presentinvention.

EXAMPLE 20

[0134] 2.45 g of Pyruvic Acid Sodium Salt (Aldrich) were diluted to 100g with water. The pH of this solution was adjusted to 7.2 by addition of15% aqueous sodium hydroxide. 0.5 g of Irgacure®-2959 was dissolved in49.5 g of this mixture. 5.00 g of polymer from Example 1 was mixed with0.75 g of this initiator solution and diluted to 6.00 g with water toafford a PEG-Urea/Irgacure® mixture containing pyruvate.

EXAMPLE 21

[0135] 3.75 g of 2-Ketoglutaric Acid Monosodium Salt (Aldrich) werediluted to 100 g with water. The pH of this solution was adjusted to 7.2by addition of 15% aqueous sodium hydroxide. 0.5 g of Irgacure®-2959 wasdissolved in 49.5 g of this mixture. 5.00 g of polymer from Example 1was mixed with 0.75 g of this initiator solution and diluted to 6.00 gwith water to afford a PEG-Urea/Irgacure® mixture containing2-ketoglutarate.

EXAMPLE 22

[0136] 2.99 g of Malic Acid (Aldrich) were diluted to 100 g with water.2.99 g of Malic Acid Disodium Salt (Aldrich) were diluted to 100 g withwater. The pH of this Malic Acid Disodium Salt solution was adjusted to7.2 by addition of a small amount of the Malic Acid solution. 0.5 g ofIrgacure®-2959 was dissolved in 49.5 g of this mixture. 5.00 g ofpolymer from Example 1 was mixed with 0.75 g of this initiator solutionand diluted to 6.00 g with water to afford a PEG-Urea/Irgacure® mixturecontaining malate buffer.

[0137] Samples of the above Examples 20, 21, and 22 were subjected to25-minute exposure to UV light, followed by autoclave at 121° C./30minutes. UV light exposure was accomplished using a Macam Lamp with aPhillips HPA 400/30 S Sunlamp bulb directed by an EFOS® Liquid LightGuide and focused on a cylindrical cell quartz cuvette as describedabove. Lamp intensity was ca. 1.8 mW/cm², and exposure time was 25minutes, implying exposure dose of 2.7 J/cm².

[0138] The samples were subjected to Ion Exchange Chromatography withthe following results: Sample Treatment HCOOH HC(O)H Irgacure UnknownsExample Pyruvate 200 115 4481172 20 Example Ketoglutarate 286 2567220 21Example Malate 187  713127 22

[0139] A blank entry in the above table means that the analyteconcentration was below detection limits. It can thus be seen from theabove examples that α-oxo-diacids have unexpected, beneficial results inregard to PEG stabilization which are not realized in the case of the anα-oxo monoacid.

EXAMPLE 23

[0140] 74.26 g of Jeffamine XTJ-501 (from Huntsman Corporation), and 3.1g of diethylene triamine (Aldrich Chemicals) were weighed into ajacketed 1-L reactor. 450 g of tetrahydrofuran (Aldrich) and 250 g ofdeionized water were added to the reactor and the contents were stirredto dissolve. The reactor was then chilled to 0° C. with stirring undernitrogen. 23.34 g of isophorone diisocyanate (Aldrich Chemicals, used asreceived) was then dissolved in 50 g of THF and added dropwise over 45minutes. The solution was stirred at temperature for one. 20 g of 20%aqueous Sodium Carbonate (Aldrich) were added to the reactor and stirredto mix. 2.8 g of acryloyl chloride (Aldrich Chemicals, used as received)was then added in one portion, and the reactor was stirred at 0° C. for30 minutes. Treatment of the reaction mixture with 20 g 20% sodiumcarbonate, followed by 2.8 g of acryloyl chloride, was repeated twicemore at 30 minute intervals. The product was then decanted to a 2-Lflask, and the reactor was chased with 400 mL of water. The mixture wasfiltered with a 40 μm sintered glass filter. The product was thenconcentrated on a rotary evaporator at 53° C./80 mBar ultimate vacuum toyield a solution essentially free of tetrahydrofuran. This solution wasthen ultrafiltered with 10 L of water using a 1-kilodalton membrane. Theresulting purified solution was then concentrated to 25.33% solids on arotary evaporator.

EXAMPLE 24

[0141] 11.76 g of Sodium Citrate Dihydrate (Aldrich) was diluted to 1.0L with water in a volumetric flask. 0.8564 g of Sodium Dihydrogencitrate(Aldrich) was diluted to 100 mL with water in a 100 mL volumetric. Bothsolutions were thus 40 mM of citrate. The Sodium Citrate Dihydratesolution was pH-adjusted to 7.2 by adding the Sodium Dihydrogencitratesolution. 8.2 g of sodium chloride was then weighed into a 1-Lvolumetric and diluted to the mark with the citrate buffer.

EXAMPLE 25

[0142] 4.76 g of Disodium Phosphate (Aldrich), 0.77 g of SodiumPhosphate (Aldrich), and 8.2 g of sodium chloride were weighed into a1-L volumetric and diluted to the mark with water.

EXAMPLE 26

[0143] 47.37 g of the 25.33% solids solution of Example 23 were weighedinto a rotary evaporator flask. 19.77 g of water were removed at 55°C./70-100 mBar. 2.4 g of initiator solution from Example 7 were addedand the mixture was agitated to homogenize.

EXAMPLE 27

[0144] 44 mg of the material afforded by Example 26 was dosed into aquartz mold and the mold was closed. The mold was then exposed to UVlight using a Macam Lamp with a Phillips HPA 400/30 S Sunlamp bulb. Theoutput of the lamp was captured by an EFOS® Liquid Light Guide andfocused into the mold. The intensity of the lamp was 1.85 mW/cm² and theexposure time was 20 s, implying an exposure energy of 37 mJ/cm². Themolds were opened and the resulting contact lens was rinsed off. Fivelenses made in this way were placed in autoclave vials which contained2.5 mL of the buffered saline of Example 24. The lenses were thensubjected to 5 autoclave cycles (121° C./30 minutes). The salines werethen combined and analyzed by ion-exclusion chromatography. The salinewas found to have 9 ppm of formic acid, a value below the OccupationalSafety and Health Administration's Short-Term Exposure Limit (STEL) of10 ppm.

EXAMPLE 28

[0145] 44 mg of the material afforded by Example 26 was dosed into aquartz mold and the mold was closed. The mold was then exposed to UVlight using a Macam Lamp with a Phillips HPA 400/30 S Sunlamp bulb. Theoutput of the lamp was captured by an EFOS® Liquid Light Guide andfocused into the mold. The intensity of the lamp was 1.85 mW/cm² and theexposure time was 20 s, implying an exposure energy of 37 mJ/cm². Themolds were opened and the resulting contact lens was rinsed off.

[0146] Five lenses made in this way were placed in autoclave vials whichcontained 2.5 mL of the buffered saline of Example 25. The lenses werethen subjected to 5 autoclave cycles (121° C./30 minutes). The salineswere then combined and analyzed by ion-exclusion chromatography. Thesaline was found to have 36 ppm of formic acid. This value is well abovethe Occupational Safety and Health Administration's Short-Term ExposureLimit (STEL) of 10 ppm, rendering the lenses unfit for use.

[0147] The utility of the organic multi-acids of the present inventionwas thus unexpectedly equivalent regardless of where in the processingthe organic multi-acids is employed.

EXAMPLE 29

[0148] Preparation of Acrylamide-Capped Polyurea

[0149] Place 2017 grams of tetrahydrofuran (THF), 1257 grams of water,420 amine group milliequilvalents (meq) of Jeffamine® XTJ501 (HunstmanChemicals), 250 amine group meq of Jeffamines® XTJ502 (HunstmanChemicals), 134 amine group meq of bis-hexamethylenetriamine (AldrichChemicals) into a jacketed 5 L reactor. At a temperature ofapproximately from 0 to 5° C., add a solution of 500 isocyanate groupmeq of isophorone diisocyanate (Aldrich Chemicals), 134 isocyanate groupmeq of VESTANAT® T1890/100 (Degussa Chemicals) and about 370 grams ofTHF drop wise with intensive stirring over about 30 minutes. Keep thesolution temperature at approximately 0 to 5° C. for approximately 25minutes. Add approximately 108 grams of a 20% sodium carbonate aqueoussolution, followed by 17 grams of acryloyl chloride (Aldrich Chemicals)to the solution. After 30 minutes, add a second aliquot of 108 grams ofsodium carbonate solution followed by 17 grams of acryloyl chloride.Discontinue cooling after the second addition. After 30 minutes, add athird aliquot of 108 grams of sodium carbonate solution followed by 3.4grams of acryloyl chloride. Thirty minutes after the final addition,drain the reaction mixture from the reactor, then rinse the reactor witha small amount of THF or water. Filter the mixture through a 17 μmsintered glass filter under vacuum. Concentrate the solution undervacuum using a rotary evaporator to yield a solution essentially free ofTHF. Ultrafilter this solution with approximately 31 L of water using a1-kilodalton membrane. Further purify the solution by passing thesolution through a 0.45 um Teflon membrane under pressure. Stabilize themacromer solution with 50 ppm of hydroxyl-TEMPO (versus the polymer).Concentrate the solution to approximately 49% solids under vacuum usinga rotary evaporator.

EXAMPLE 30

[0150] Dissolve 1.875 g of 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy,free radical (hereafter, 4-hydroxy-TEMPO) in 25 mL of water.

EXAMPLE 31

[0151] Preparation of Formulation. Mix 19.47 grams of the polymersolution from Example 29 (49.3% polymer), 0.0576 grams of the solutionfrom Example 30, 1.92 grams of the solution from Example 7, 7.67 gramsof D.I. water, and 1.58 grams of visitint solution. Place theformulation containing 32% polymer, 80 ppm of 4-hydroxy-TEMPO, 0.2%Irgacure and 42 ppm of visitint into 5 mL syringes and centrifuge for 15minutes at 4500 rpm.

EXAMPLE 32

[0152] Preparation of Formulation containing CBS. Mix 6.49 grams of thepolymer solution from Example 29, 0.0192 grams of the solution fromExample 30, 0.64 grams of the solution from Example 7, 2.69 grams of 60mM CBS described in Example 37, and 0.158 grams of visitint solution.Place the formulation containing 32% polymer, 80 ppm of 4-hydroxy-TEMPO,0.2% Irgacure, 16 mM of CBS, and 42 ppm of visitint into 5 mL syringesand centrifuge for 15 minutes at 4500 rpm.

EXAMPLE 33

[0153] Preparation of Contact Lenses. Place about 2 drops of theformulation from Example 31 (or Example 32) into a quartz mold (−1.0diopters). Irradiate the formulation with 17 mJ of energy using theMacam lamp described in Examples 19. Place the resulting lenses into0.85 mL of various buffer solutions. Use fifteen lenses for each buffersolution. Autoclave five lenses with buffer solution once, five lenses 3times and five lenses 5 times. Each autoclave cycle is 121° C. for 30minutes.

EXAMPLE 34

[0154] Preparation of 20 mM Citrate Buffered Saline CBS. Weigh 5.88grams of sodium citrate dihydrate (Aldrich Chemicals), 0.060 grams ofSodium Dihydrogencitrate (Aldrich), and 7.70 grams of sodium chlorideinto a 1-L volumetric flask and dilute to the mark with D.I. water. ThepH of the solution is 7.05 and the osmolarity is 300 mOsm.

EXAMPLE 35

[0155] Preparation of 40 mM Citrate Buffered Saline CBS. Weigh 11.76grams of sodium citrate dihydrate (Aldrich Chemicals), 0.121 grams ofSodium Dihydrogencitrate (Aldrich), and 5.90 grams of sodium chlorideinto a 1-L volumetric flask and dilute to the mark with D.I. water. ThepH of the solution is 7.08 and the osmolarity is 302 mOsm.

EXAMPLE 36

[0156] Preparation of 40 mM Citrate Buffered Saline CBS at low pH. Weigh0.420 grams of citric acid monohydrate (Aldrich Chemicals), 0.428 gramsof Sodium Dihydrogencitrate (Aldrich), and 0.70 grams of sodium chlorideinto a 100 mL volumetric flask and dilute to the mark with D.I. water.The pH of the solution is 3.67 and the osmolarity is 292 mOsm.

EXAMPLE 37

[0157] Preparation of 60 mM Citrate Buffered Saline CBS. Weigh 17.64grams of sodium citrate dihydrate (Aldrich Chemicals), 0.182 grams ofSodium Dihydrogencitrate (Aldrich), and 4.20 grams of sodium chlorideinto a 1-L volumetric flask and dilute to the mark with D.I. water. ThepH of the solution is 7.10 and the osmolarity is 306 mOsm.

EXAMPLE 38

[0158] Measurement of formic acid concentration. Combine the buffersolution of 2 lenses from each condition and test for formic acid usingthe method described in Example 18. Table 4 lists the average amount offormic acid in ppm from 2 different samples. The detection limit of theinstrument is 0.3 ppm 40 mM Number 40 mM w/CBS 40 mM of auto- 20 CBS 40in 60 40 CBS clave mM with mM formu- mM mM with no cycles CBS low pH CBSlation CBS PBS water lens 1 <0.3 <0.3 <0.3 0.6 <0.3 4.7 7.0 <0.3 3 1.13.5 2.9 8.8 6.8 135 17.0 0.6 5 5.0 5.0 8.4 14.8 14.3 191 106.0 3.6

[0159] The addition of citrate buffered saline at all concentrationsused reduces the amount of formic acid formed by the lenses versus waterand PBS. The effect is most obvious at 5 autoclave cycles where theformic acid concentration is more than an order of magnitude higher inwater or PBS than in 40 mM CBS. CBS also functions to reduce theformation of formic acid during the at low pH (3.67) using similarconditions. CBS concentrations of 20, 40 and 60 mM are all acceptable.Having CBS in the formulation during the UV cure does not further reducethe concentration of formic acid after 5 autoclave cycles versus 60 mMCBS.

[0160] Although various embodiments of the invention have been describedusing specific terms, devices, and methods, such description is forillustrative purposes only. The words used are words of descriptionrather than of limitation. It is to be understood that changes andvariations may be made by those skilled in the art without departingfrom the spirit or scope of the present invention, which is set forth inthe following claims. In addition, it should be understood that aspectsof the various embodiments may be interchanged either in whole or inpart. Therefore, the spirit and scope of the appended claims should notbe limited to the description of the preferred versions containedtherein.

What is claimed is:
 1. A medical device comprising: apoly(oxyalkylene)-containing polymeric material and a biocompatibleorganic multi-acid or biocompatible salt thereof, wherein thepoly(oxyalkylene)-containing polymeric material has a polymer networkhaving at least one unit of formula (I)—O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I) wherein R₁, R₂, and R₃,independently of one other, are each linear or branched C₂-C₄-alkylene,and n, m and p, independently of one another, are each a number from 0to 100, wherein the sum of (n+m+p) is 5 to 1000; wherein thebiocompatible organic multi-acid or biocompatible salt thereof isdistributed within the poly(oxyalkylene)-containing polymeric materialbut not crosslinked to the polymer network, and wherein thebiocompatible organic multi-acid or biocompatible salt thereof ispresent in an amount effective to improve the stability of the medicaldevice so that the medical device has a decreased susceptibility tooxidative degradation, characterized by having at least an 1.5-foldreduction of the amount of detectable formic acid and optionally otherdegradation by-products.
 2. A medical device of claim 1, wherein themedical device is an ophthalmic device.
 3. A medical device of claim 1,wherein the biocompatible organic multi-acid is selected from the groupconsisting of hydroxy diacids, hydroxy triacids, and amino acids.
 4. Amedical device of claim 3, wherein the biocompatible organic multi-acidis an α-oxo-multi-acid.
 5. A medical device of claim 4, wherein theα-oxo-multi-acid is selected from the group consisting of citric acid,2-ketoglutaric acid, and malic acid.
 6. A medical device of claim 5,wherein the medical device of the invention is a copolymerizationproduct of a composition comprising (a) a prepolymer containingethylenically unsaturated groups and at least one poly(oxyalkylene) unitof formula (I); (b) a water-soluble and biocompatible organic multi-acidor biocompatible salt thereof in an amount sufficient to improve thestability of a poly(oxyalkylene)-containing polymeric material made fromthe composition; (c) optionally a photoinitiator or a thermal initiator;and (d) optionally one or more vinylic monomers.
 7. A medical device ofclaim 6, wherein the prepolymer is a crosslinkable polyurea.
 8. Amedical device of claim 6, wherein the prepolymer is a crosslinkablepolyurethane.
 9. A medical device of claim 6, wherein the medical deviceis an ophthalmic device.
 10. A medical device of claim 5, wherein thebiocompatible organic multi-acid or biocompatible salt thereof isimpregnated within the poly(oxyalkylene)-containing polymeric material,wherein the poly(oxyalkylene)-containing polymeric material is apolymerization product of a reactive mixture comprising (a) a monomer orprepolymer having at least one poly(oxyalkylene) unit of formula (I) andfunctional groups which are amino, hydroxyl or isocyanato groups, and(b) an organic diamine, an organic polyamine, an organic diol, anorganic polyol, an organic diisocyante, or organic polyisocyanate,provided that components (a) and (b) react with each other to form apolyurea and/or polyurethane network.
 11. A medical device of claim 10,wherein the medical device is an ophthalmic device.
 12. A method forproducing a medical device, comprising the steps of: (1) obtaining apolymerizable fluid composition comprising (a) a prepolymer havingethylenically unsaturated groups and at least one poly(oxyalkylene) unitof formula (I) —O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I) wherein R₁, R₂,and R₃, independently of one other, are each linear or branchedC₂-C₄-alkylene, and n, m and p, independently of one another, are each anumber from 0 to 100, wherein the sum of (n+m+p) is 5 to 1000, (b) abiocompatible organic multi-acid or biocompatible salt thereof, (c)optionally a photoinitiator or a thermal initiator, and (d) optionallyone or more vinylic monomers; (2) introducing an amount of thepolymerizable fluid composition in a mold for making the medical device;and (3) actinically or thermally polymerizing the polymerizable fluidcomposition in the mold to form the medical device having a polymernetwork having at least one unit of formula (I) and the biocompatibleorganic multi-acid or biocompatible salt thereof which is notcrosslinked to the polymer network, wherein the biocompatible organicmulti-acid or biocompatible salt thereof is present in an amounteffective to improve the stability of the medical device so that themedical device has a decreased susceptibility to oxidative degradationcharacterized by having at least an 1.5-fold reduction of the amount ofdetectable formic acid and optionally other degradation by-products. 13.The method of claim 12, wherein the medical device is an ophthalmicdevice.
 14. The method of claim 13, wherein the biocompatible organicmulti-acid is selected from the group consisting of hydroxy diacids,hydroxy triacids, olefinic diacids, olefinic tri-acids, and amino acids.15. The method of claim 14, wherein the biocompatible organic multi-acidis an α-oxo-multi-acid.
 16. The method of claim 15, wherein theα-oxo-multi-acid is selected from the group consisting of citric acid,2-ketoglutaric acid, and malic acid.
 17. The method of claim 15, whereinthe prepolymer is a crosslinkable polyurea
 18. The method of claim 15,wherein the prepolymer is a crosslinkable polyurethane.
 19. The methodof claim 16, further comprising the steps of removing the medical devicefrom the mold and hydrating the medical device in an aqueous solutioncontaining the α-oxo-multi-acid or biocompatible salt thereof.
 20. Themethod of claim 19, wherein the aqueous solution has an osmolarity ofabout 200 to 450 milli-osmole in 1000 ml (unit: mOsm/ml).
 21. The methodof claim 15, further comprising a step of sterilizing the medical devicein an aqueous solution containing the α-oxo-multi-acid or biocompatiblesalt thereof.
 22. The method of claim 21, wherein the aqueous solutionhas an osmolarity of about 200 to 450 milli-osmole in 1000 ml (unit:mOsm/ml).
 23. A method for producing a medical device, comprising thesteps of: (1) introducing a reactive mixture into a mold by using aReaction Injection Molding (RIM) process to form the medical device,wherein the reactive mixture comprises (a) a monomer or prepolymerhaving functional groups and at least one poly(oxyalkylene) unit offormula (I) —O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I) in which R₁, R₂,and R₃, independently of one other, are each linear or branchedC₂-C₄-alkylene, and n, m and p, independently of one another, are each anumber from 0 to 100, wherein the sum of (n+m+p) is 5 to 1000, whereinthe functional groups are amino, carboxy, hydroxy or isocyanato groups,and (b) an organic diamine, an organic polyamine, an organic diacid, anorganic polyacid, an organic diol, an organic polyol, an organicdiisocyante, or organic polyisocyanate, provided that components (a) and(b) react with each other to form a polyurea and/or polyurethanenetwork; (2) removing the medical device from the mold; and (3)impregnating the medical device with a biocompatible organic multi-acidor biocompatible salt thereof in an amount effective to improve thestability of the medical device so that the medical device has adecreased susceptibility to oxidative degradation characterized byhaving at least an 1.5-fold reduction of the amount of detectable formicacid and optionally other degradation by-products.
 24. The method ofclaim 23, wherein the medical device is an ophthalmic device.
 25. Themethod of claim 24, wherein the biocompatible organic multi-acid is anα-oxo-multi-acid.
 26. The method of claim 25, wherein the impregnatingstep is achieved by immersing the medical device for a period of time inan aqueous solution containing the α-oxo-multi-acid or biocompatiblesalt thereof.
 27. The method of claim 24, wherein the reactive mixturefurther comprises one or more prepolymers having ethylenicallyunsaturated groups or one or more vinylic monomers to form a differentpolymer network which interpenetrates the polyurea and/or polyurethanenetwork.
 28. A stabilized poly(oxyalkylene)-containing polymericmaterial, comprising: (a) a polymer network having at least one unit offormula (I) —O—(R₁—O)_(n)—(R₂—O)_(m)—(R₃—O)_(p)—  (I) wherein R₁, R₂,and R₃, independently of one other, are each linear or branchedC₂-C₆-alkylene, and n, m and p, independently of one another, are each anumber from 0 to 100, wherein the sum of (n+m+p) is 5 to 1000; and (b) abiocompatible organic multi-acid or biocompatible salt thereof presentin an amount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymeric material, which is distributedwithin the polymeric material but not crosslinked to the polymernetwork.
 29. The stabilized poly(oxyalkylene)-containing polymericmaterial of claim 28, wherein the biocompatible organic multi-acid isselected from the group consisting of hydroxy diacids, hydroxy triacids,and amino acids.
 30. The stabilized poly(oxyalkylene)-containingpolymeric material of claim 28, wherein the biocompatible organicmulti-acid is an α-oxo-multi-acid.
 31. The stabilizedpoly(oxyalkylene)-containing polymeric material of claim 30, wherein theα-oxo-multi-acid is selected from the group consisting of citric acid,2-ketoglutaric acid, and malic acid.
 32. The stabilizedpoly(oxyalkylene)-containing polymeric material of claim 30, wherein thestabilized poly(oxyalkylene)-containing polymeric material is acopolymerization product of a composition comprising: (a) a prepolymercontaining ethylenically unsaturated groups and at least one unit offormula (I); and (b) the α-oxo-multi-acid or biocompatible salt thereofin an amount effective to improve the stability of the medical device sothat the medical device has a decreased susceptibility to oxidativedegradation characterized by having at least an 1.5-fold reduction ofthe amount of detectable formic acid and optionally other degradationby-products.
 33. The stabilized poly(oxyalkylene)-containing polymericmaterial of claim 30, wherein the stabilizedpoly(oxyalkylene)-containing polymeric material is apoly(oxyalkylene)-containing polymeric material impregnated with theα-oxo-multi-acid or biocompatible salt thereof in an amount effective toimprove the stability of the medical device so that the medical devicehas a decreased susceptibility to oxidative degradation characterized byhaving at least an 1.5-fold reduction of the amount of detectable formicacid and optionally other degradation by-products, wherein thepoly(oxyalkylene)-containing polymeric material is a copolymerizationproduct of a composition comprising: (a) a prepolymer containingethylenically unsaturated groups and at least one unit of formula (I)and (b) optionally one or more vinylic monomers.
 34. The stabilizedpoly(oxyalkylene)-containing polymeric material of claim 30, wherein thestabilized poly(oxyalkylene)-containing polymeric material is apoly(oxyalkylene)-containing polymeric material impregnated with theα-oxo-multi-acid or biocompatible salt thereof in an amount effective toimprove the stability of the medical device so that the medical devicehas a decreased susceptibility to oxidative degradation characterized byhaving at least an 1.5-fold reduction of the amount of detectable formicacid and optionally other degradation by-products, wherein thepoly(oxyalkylene)-containing polymeric material is polymerizationproduct of a reactive mixture, wherein the reactive mixture comprises(a) a monomer or prepolymer having at least one poly(oxyalkylene) unitof formula (I) and functional groups which are amino, carboxy, hydroxylor isocyanato groups and (b) an organic diamine, an organic polyamine,an organic diacid, an organic polyacid, an organic diol, an organicpolyol, an organic diisocyante, or organic polyisocyanate, provided thatcomponents (a) and (b) react with each other to form a polyurea and/orpolyurethane network.
 35. A method for sterilizing a medical devicehaving a core material and/or a coating, wherein the core material andthe coating, independently of each other, are made of apoly(oxyalkylene)-containing polymeric material, the method comprising:autoclaving the medical device in a solution containing a water-solubleand biocompatible organic multi-acid or biocompatible salt thereof in anamount sufficient to improve the stability of thepoly(oxyalkylene)-containing polymeric material, so that thepoly(oxyalkylene)-containing polymeric material has a decreasedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.
 36. The method of claim 35,wherein wherein the biocompatible organic multi-acid is selected fromthe group consisting of hydroxy diacids, hydroxy triacids, olefinicdiacids, olefinic tri-acids, and amino acids.
 37. The method of claim36, wherein the biocompatible organic multi-acid is an α-oxo-multi-acid.38. The method of claim 37, wherein the α-oxo-multi-acid is selectedfrom the group consisting of citric acid, 2-ketoglutaric acid, and malicacid.
 39. The method of claim 38, wherein the solution has an osmolarityof from about 200 to 450 milli-osmole in 1000 ml (unit: mOsm/ml).
 40. Anaqueous solution for sterilizing and/or storing an ophthalmic device,wherein the ophthalmic device is made of a poly(oxyalkylene)-containingpolymeric material, the aqueous solution having: a biocompatible organicmulti-acid or biocompatible salt thereof in an amount sufficient toimprove the stability of the poly(oxyalkylene)-containing polymericmaterial; an osmolarity of about 200 to 450 milli-osmole in 1000 ml(unit: mOsm/ml), wherein the aqueous solution is capable of improvingthe stability of the poly(oxyalkylene)-containing polymeric material, sothat the poly(oxyalkylene)-containing polymeric material has a reducedsusceptibility to oxidative degradation characterized by having at leastan 1.5-fold reduction of the amount of detectable formic acid andoptionally other degradation by-products.
 41. The aqueous solution ofclaim 40, wherein the osmolarity of the aqueous solution is from about250 to 350 mOsm/l.